Previous studies have emphasized that after brain and spinal cord injury there are dramatic reductions in levels of the second messenger cyclic adenosine monophosphate (cAMP), a critical intracellular signaling molecule in neurons and inflammatory cells. Over the last funding period, our laboratory has found that after traumatic brain injury (TBI) reductions in cAMP participate in the vulnerability of the posttraumatic brain to secondary injuries such as hemodynamic alterations, inflammation and long-term synaptic dysfunction. Phosphodiesterase 4 (PDE4) is the major enzyme responsible for cAMP hydrolysis in the brain and currently is an important molecular target for the treatment of various human neurological diseases including neurotrauma and Alzheimer's disease. PDE4 inhibitors improve chronic learning and memory deficits after TBI and reverse learning deficits in an APP/PS1 transgenic mouse model of Alzheimer's disease. In the current proposal, we will address several knowledge gaps that hamper clinical development of PDE4 inhibitors for the treatment of TBI and Alzheimer's disease, including the involvement of specific PDE4 isoforms in cognitive dysfunction. The overall hypothesis of this proposal is that a PDE4 isoform-selective inhibitor will improve chronic cognitive deficits after TBI in wild type mice and in a mouse model of Alzheimer's disease. To test this hypothesis, we propose to utilize APP/PS1 mice which recapitulate several features of Alzheimer's disease. Furthermore, these mice have exacerbated pathology and inflammation after TBI. These studies will determine which specific PDE4 isoforms need to be selectively inhibited during in the evolution of Alzheimer's disease after TBI to promote cognitive recovery, prevent inflammation and reduce axonal damage. This proposal is supported by a multidisciplinary, multi- institutional research team with experience in experimental TBI models, Alzheimer's disease mouse models and a pharmacological partner with an established record in CNS drug discovery. These studies will provide the necessary preclinical data for the clinical translation of these novel agents for the treatment of TBI and Alzheimer's disease.